Anti-allergic pharmaceutical compositions

ABSTRACT

2-Nitroindane-1,3-dione derivatives are useful in the prophylaxis and treatment of asthma, hay fever and also in the treatment of rhinitis.

This invention relates to pharmaceutical compositions which are useful in the inhibition of the effects of certain types of antigen-antibody reactions, and are therefore useful in the prophylaxis and treatment of diseases associated with allergic or immunological reactions, e.g. certain types of asthma and hay-fever, and also in the treatment of rhinitis.

We have discovered that certain derivatives of 2-nitroindane-1,3-dione have useful activity in warm-blooded mammals in that they inhibit the effects of certain types of antigen-antibody reactions. In particular, they appear to inhibit the release of mediator substances, such as histamine, which are normally released after antigen-antibody combinations and which normally mediate the allergic response. The class of 2-nitroindane-1,3-dione derivatives which we have found to be active in this way has formula (I): ##SPC1##

and the salts of compounds (I) are also active. In formula (I), R₁, R₂, R₃, and R₄ are each hydrogen or alkyl, alkoxy, aryl, aralkyl, heterocyclic or halogen groups, or any two adjacent groups R₁ and R₂, R₂ and R₃, or R₃ and R₄ taken together represent the residue of a substituted or unsubstituted carbocyclic or heterocyclic ring system. However, a search of the chemical literature has revealed that not all of the members of class (I) are novel compounds. Below we list those compounds of formula (I) which are mentioned in the literature, together with the appropriate literature reference:

(I): R₁ = R₂ = R₃ = R₄ = H

(i): r₁ = r₂ = och₃ ; r₃ = r₄ = h chem.Abs. 1961, 55, 476g

(I): R₂ = OCH₃ ; R₁ = R₃ = R₄ = H Chem.Abs. 1968, 68, 87034q

(I): R₁ = Cl; R₂ = R₃ = R₄ = H Chem.Abs. 1969, 70, 11379b

(I): R₂ = Cl; R₁ = R₃ = R₄ = H Chem.Abs. 1969, 70, 37507s

(I): R₂ = Br; R₁ = R₃ = R₄ = H Chem.Abs. 1972, 132349s

(I): R₁ = CH₃ ; R₂ = R₃ = R₄ = H Latv. PSR Zinat Akad, Vestis (Khim Ser) 1971, 425-30

(I): R₂ = I; R₁ = R₃ = R₄ = H ibid 1971, 179-181

In the above list, no reference has been given for the first compound, i.e. 2-nitroindane-1,3-dione itself which is, of course, a common laboratory reagent.

Although the above compounds are reported in the literature, no form of useful biological activity has been ascribed to them. Likewise there has been in the literature no suggestion that such compounds are likely to possess any form of useful biological activity, and in particular the discovery that they have anti-allergic activity has not been predicted in any way.

Accordingly, the present invention provides in its broadest aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##SPC2##

together with one or more pharmaceutically acceptable carriers, in which formula R₁, R₂, R₃ and R₄ represent hydrogen, lower alkyl, lower alkoxy, aryl, aralkyl, heterocyclic or halogen groups, and any two adjacent groups R₁ and R₂, and R₃ or R₃ and R₄ may be joined in a carbocyclic or heterocyclic ring system, this definition of R₁, R₂, R₃ and R₄ being subject to the proviso that R₁, R₂, R₃ and R₄ are not simultaneously hydrogen.

It will be noted that the above definition of the compositions of this invention specifically excludes compositions 2-nitroindane-1,3-dione itself. This exclusion is necessary since such compositions are claimed in a different pending patent application commonly assigned.

The compositions of this invention may be presented as a microfine powder for insufflation, e.g. as a snuff or in capsules of hard gelatine. They may also be presented together with a sterile liquid carrier for injection. Some of the compounds of formula (I) appear to be active when given by the oral route and thus the compositions of this invention may be in the form of tablets, capsules, pills or syrups. Preferably the compositions of this invention are presented in unit dosage form, or in a form in which the patient can administer to himself a single dosage. If desired, a small amount of bronchodilator compound may be incorporated in the compositions of the invention, both to inhibit the cough response if the composition is insufflated and to provide immediate relief during an asthmatic attack. The effective dose of compound (I) depends on the particular compound employed, but is generally in the range of from 0.1 mg/kg/day to 100 mg/kg/day.

The precise nature of the pharmaceutical carrier used in the composition of this invention is not important. Standard pharmaceutical practice may be followed, but it is perhaps worth noting that if the composition is to be administered by insufflation, a microfine powder where substantially all the particles have diameters of less than 50 microns is preferred.

The present invention also provides, in another of its aspects compounds of formula (I) and salts thereof: ##SPC3##

wherein R₁, R₂, R₃ and R₄ are each hydrogen or alkyl, alkoxy, aryl, aralkyl, heterocyclic or halogen groups, or any two adjacent groups, R₁ and R₂, R₂ and R₃, R₃ and R₄ may be joined in a carbocyclic or heterocyclic ring system, with the exception of the following compounds and salts thereof:

2-nitroindane-1,3-dione

4,5-dimethoxy-2-nitroindane-1,3-dione

5-methoxy-2-nitroindane-1,3-dione

4-chloro-2-nitroindane-1,3-dione

5-chloro-2-nitroindane-1,3-dione

5-bromo- 2-nitroindane-1,3-dione

4-methyl-2-nitroindane-1,3-dione

5-iodo-2-nitroindane-1,3-dione

Hereafter in this specification when the phrase "the compounds of this invention" is used, it is to be understood that we mean compounds of formula (I) and salts thereof excluding the eight compounds specifically listed above, and their salts.

Examples of groups R₁, R₂, R₃ and R₄ which may be present in the compounds of this invention include methyl, ethyl, n- and iso-propyl, n-, sec- and tert- butyl; methoxy, ethoxy, n- and iso- propoxy, n-, sec- and tert- butoxy, phenyl, benzyl, pyridyl, fluoro, chloro, bromo or iodo groups. In addition R₁ and R₂ and R₂ and R₃ or R₃ and R₄ taken together may represent the residue of a 1,2-phenylene or 1,2-cyclohexylene ring, which may carry one or more of the substituents listed above.

Compounds of the present invention which are especially preferred for their high activity include the following compounds and their pharmaceutically acceptable salts:

5,6-dimethyl-2-nitroindane-1,3-dione;

2-nitrobenz[f]indane-1,3-dione;

4-methoxy-6-ethyl-2-nitroindane-1,3-dione;

4-n-butoxy-2-nitroindane-1,3-dione;

4,6-dimethyl-2-nitroindane-1,3-dione;

5-methyl-2-nitroindane-1,3-dione;

4-fluoro-2-nitroindane-1,3-dione;

In the preceeding paragraphs, we have referred to pharmaceutically acceptable salts of the compounds of formula (I). Such salts include the alkali metal salts e.g. sodium or potassium, and salts with organic bases such as amines or amino compounds. These compounds may, on occasions, be capable of existing in an anhydrous form or one or more hydrates. The invention includes all of these forms.

The compounds of this invention may be prepared by a process which comprises nitrating the parent indane-1,3-dione of formula (III): ##SPC4##

wherein R₁, R₂, R₃ and R₄ are as hereinbefore defined. The nitration step may be carried out at various temperatures although usually below 25°C. In general a temperature range of from -20°C to +20°C will be suitable, with +10°C being preferred.

The starting materials of formula (III) above may be prepared by known methods, the choice of method being dependent on the nature of the substituents present. With a single relatively chemically inert substituent such as a methyl, methoxy, or phenyl radical, the method of choice is the Claisen condensation wherein a compound of formula (IV): ##SPC5##

wherein R is the inert substituent and X is an alkyl group is reacted with ethyl acetate.

With alkyl or alkoxy substituents in both the 3- and 6- position of (IV) the Claisen condensation may sometimes afford only low yields of the required diones and the same is true for the 4,5-methylenedioxy analogue. In such cases the preferred method involves the reaction of a compound formula (V), formed from the appropriate anhydride and acetic anhydride ##SPC6##

wherein both R₁ and R₂ are 4- or 7 - alkyl or alkoxy groups or R₁ R₂ is a 5,6-methylenedioxy group with a strong base such as sodium methoxide.

Neither of the above procedures is advisable in the presence of halogen functions, and here the Knoevenagel reaction is best suited. This involves the reaction of an active methylene compound with a compound of formula (VI): ##SPC7##

wherein R₁, R₂, R₃ and R₄ are the same or different and each is hydrogen or a halogen group. The use of ethyl acetoacetate as the active methylene compound is most convenient (and economical) but has led to difficulties with both the 4-bromo and tetrachloro compounds, in which the carbethoxy intermediates are isolated ( (VII) and (VIII) respectively) ##SPC8##

For this reason, ethyl acetoacetate has been replaced by the more easily removable t-butyl acetoacetate with complete success.

The following Examples illustrate the preparation of some of the compounds of this invention (and also a few of the previously known compounds listed above) and illustrate the biological activity of such compounds.

EXAMPLE 1 a. 4-Methyl indane-1,3-dione

To a 50% dispersion of sodium hydride in mineral oil (8.2 g; 0.17 mole of NaH) was added a solution of diethyl 3-methyl phthalate (28 g; 0.119 mole) in ethyl acetate (40 ml) and the mixture refluxed with occasional swirling on a steam bath for 4 hr. After cooling, the bright yellow sodium salt was filtered and washed with a little cold ethyl acetate. To the dried sodium salt (ca 27.2 g) was added rapidly a hot (80°C) solution of hydrochloric acid (48 ml) in water (480 ml) and the product kept at 70°C until decarboxylation ceased (7 mins), cooled to 5°C, and the pale yellow solid filtered and washed with water. Recrystallisation from benzene afforded a pale yellow crystalline solid, m.p. 125°-8°C. (Found; C, 75.38; H, 5.04; C₁₀ H₈ O₂ requires; C, 74.99; H, 5.03%).

b. 4-Methyl-2-nitroindane-1,3-dione

To a stirred suspension of 4-methyl-1,3-indanedione (1.02g.0.006 mole) in anhydrous ether (5 ml) at ca 10°C was added dropwise and with stirring fuming nitric acid (2.0 ml). After 10 mins. a clear, dark solution formed followed by precipitation of a bright yellow solid. The mass was filtered and washed with 5N hydrochloric acid. Recrystallisation from water/hydrochloric acid afforded the title compound, m.p. 108°-9°C. (Found; C, 56.16; H, 3.74; N, 6.32; C₁₀ H₇ NO₄.1/2H₂ O requires; C, 56.07; H, 3.76; N, 6.54%).

EXAMPLE 2 a. 5-Methyl indane-1,3-dione

This was prepared as in Example 1(a) from diethyl 4-methyl phthalate, m.p. (benzene) 114°-116°C. (Found; C, 75.04; H, 5.19; C₁₀ H₈ O₂ requires; C, 74.99; H, 5.03%).

b. 5-Methyl-2-nitroindane-1,3-dione

Nitration of 5-methyl indane-1,3-dione as in Example 1(b) yeilded the nitro product, m.p. (water/hydrochloric acid) 115°-117°C. (Found; C, 58.43; H, 3.39; N, 6.86; C₁₀ H₇ NO₄ requires; C, 58.54; H, 3.44; N, 6.83%).

EXAMPLE 3 a. 4-Methoxy indane-1,3-dione

Dimethyl-3-methoxy phthalate (13.8 g; 0.062 mole) in ethyl acetate (20 ml) was added to a 50% dispersion of sodium hydride in mineral oil (4.1 g; 0.085 mole of NaH) and the mixture refluxed for 4 hr. in a water bath. After cooling the red oil was treated with water and the yellow solid filtered and washed well with cold water. The sodium salt (15.8 g) was decarboxylated with 5N hydrochloric acid (23 ml) at 70°C. M.p. (benzene) 145°-147°C (d). (Found; C, 68.22; H, 4.63; C₁₀ H₈ O₃ requires; C, 68.18; H, 4.58%).

b. 4-Methoxy-2-nitro indane-1,3-dione

Nitration of 4-methoxy indane-1,3-dione as in Example 1(b) afforded the title compound, m.p. (water, hydrochloric acid) 132°-4°C. (Found; C, 54.39; H, 3.22; N, 6.42; C₁₀ H₇ NO₅ requires; C, 54.32; H, 3.19; N, 6.33%).

EXAMPLE 4 a. 4-Ethoxy indane-1,3-dione

Dimethyl 3-ethoxy phthalate (m.p. 58°C) was converted into 4-ethoxy indane-1,3-dione according to Example 1(a), m.p. (benzene) 111°C. (Found; C, 69.48; H, 5.34; C₁₁ H₁₀ O₃ requires; C, 69.46; H, 5.30%).

b. 4-Ethoxy-2-nitro indane-1,3-dione

Direct nitration of 4-ethoxy indane-1,3-dione with fuming nitric acid as in Example 1(b) gave the 2-nitro derivative, m.p. (water, hydrochloric acid) 95°-96°C. (Found; C, 48.83; H, 4.81; N, 4.97; C₁₀ H₉ NO₅. 2H₂ O requires; C, 48.71; H, 4.83; N, 5.17%).

EXAMPLE 5 a. Benz[f] indane-1,3-dione

This was prepared by an analagous procedure to that described in Example 1(a), m.p. 136°C (d) from benzene. (Found; C, 73.80; H, 4.15; C₁₃ H₈ O₂.H₂ O requires; C, 72.89; H, 4.71%).

b. 2-Nitro benz[f]indane-1,3-dione

Nitration of benz[f] indane-1,3-dione with fuming nitric acid in ether at 10°C afforded the title compound, m.p. (water, hydrochloric acid) 163°-4°C. (Found; C, 64.89; H, 3.06; N, 5.03; C₁₃ H₇ NO₄ requires; C, 64.74; H, 2.93; N, 5.81%).

EXAMPLE 6 a. 3-Methoxy-6-methyl phthalalyl acetic acid

3-Methoxy-6-methyl phthalic anhydride (21.29 g; 0.11 mole) was treated with freshly fused potassium acetate (16.7 g) and acetic anhydride (35 ml). The resulting mixture was heated for 1 hr. at 100°C and then for a further 4 hrs. at 150°-5°C. After cooling water (100 ml) was added and the dark precipitate filtered and washed well with cold water and methanol until the filtrate was almost colourless; the solid was extracted with 5% aqueous sodium bicarbonate (500ml) and the filtered extract acidified. A pale yellow precipitate of the phthalalylacetic acid separated in quantitative yield, m.p. (dioxan) 260°-2°C (d). (Found; C, 61.13; H, 4.40; C₁₂ H₁₀ O₅ requires; C, 61.54; H, 4.30%).

b. 4-Methoxy-7-methyl indane-1,3-dione

Sodium methoxide [from sodium (10.8g)] in methanol (100 ml) was added with vigorous shaking to a solution of 3-methoxy-6-methyl phthalalyl acetic acid (10.8 g; 0.046 mole) in methanol (250 ml) and the mixture stood at ambient temperature for 2 hrs. The resulting orange gel was heated for 5 hrs. at 100°C, cooled and then filtered. On addition of hot (80°C) 5N hydrochloric acid (160 ml) spontaneous decarboxylation ensued and an orange-yellow solid formed. Filtration and recrystallisation (benzene) afforded the indanedione, m.p. 172°C as a buff solid. (Found; C, 69.50; H, 5.34; C₁₁ H₁₀ O₃ requires; C, 69.46; H, 5.30%).

c. 4-Methoxy-7-methyl-2-nitro indane-1,3-dione

Treatment with 4-methoxy-7-methyl indane-1,3-dione with fuming nitric acid as in Example 1(b) gave the 2-nitro derivative as a yellow solid, m.p. (water, hydrochloric acid) 143°-146°C. (Found; C, 56.61; N, 3.93; N, 5.80; C₁₁ H₉ NO₅ requires; C, 56.18; H, 3.86; N, 5.96%).

EXAMPLE 7 a. 5-Bromo indane-1,3-dione

A solution of 4-bromo phthalic anhydride (4.15 g; 0.018 mole) in acetic anhydride (10 g) containing triethylamine (4 g) was treated at room temperature with ethyl acetoacetate (2.38g; 0.02 mole). After 24 hrs. with stirring, crushed ice (20 g) and concentrated hydrochloric acid (10 ml) were added and the precipitated red solid filtered. Addition of a hot (70°-80°C) solution of hydrochloric acid (150 ml) in water (750 ml) to this solid resulted in decarboxylation and generation of 5-bromo indane-1,3-dione as red plates, m.p. (acetone) 152°-3°C. (Found; C, 48.04; H, 2.17; Br, 35.63; C₉ H₅ Br O₂ requires; C, 48.05; H, 2.24; Br, 35.52%).

b. 5-Bromo-2-nitro indane-1,3-dione

Nitration as described in Example 1(b) converted 5-bromo indane-1,3-dione to its 2-nitro derivative, m.p. (water, hydrochloric acid) 127°-9°C. (Found; C, 40.03; H, 1.55; N, 5.11, Br, 29.32; C₉ H₄ Br NO₄ requires; C, 40.01, H, 1.49; N, 5.18; Br, 29.58%).

EXAMPLE 8 a. 4-Bromo indane-1,3-dione

A modification of the procedure used in Example 7(a) in which ethyl acetoacetate was replaced by t-butyl acetoacetate afforded 4-bromo indane-1,3-dione from the anhydride, decomposes above 120°C.

b. 4-Bromo-2-nitro indane-1,3-dione

This was prepared as for the 5-bromo isomer m.p. (water, hydrochloric acid) 127°-8°C. (Found; C, 40.16; H, 1.60; N, 5.36; Br, 28.65; C₉ H₄ Br NO₄ requirements; C, 40.01; H, 1.49; N, 5.18; Br, 29.58%).

EXAMPLE 9 a. 4-Fluoro indane-1,3-dione

Using the procedure outlined in Example 8a gave 4-fluoro indane-1,3-dione m.p. (benzene) 117°-118°C from 4-fluoro phthalic anhydride. (Found; C, 65.87; H, 3.15; C₉ H₅ FO₂ requires; C, 65.86; H, 3.07%).

b. 4-Fluoro-2-nitro indane-1,3-dione

The title compound was formed by nitration of 4-fluoro indane-1,3-dione at 10°C, m.p. (water, hydrochloric acid) 124°C. (Found; C, 47.75; H, 2.68; N, 6.19; C₉ H₄ F NO₄.H₂ 0 requires; C, 47.59; H, 2.66; N, 6.17%).

EXAMPLE 10 a. 4,5,6,7-Tetrachloro indane-1,3-dione

Tetrachloro phthalic anhydride was converted to the indane dione by the method described in Example 8(a), decomposes on heating. (Found; C, 39.01; H, 0.75; Cl, 50.15; C₉ H₂ Cl₄ O₂ requires: C, 38.07; H, 0.71; Cl, 49.60%).

b. 2-Nitro-4,5,6,7-tetrachloro indane-1,3-dione

Nitration of 4,5,6,7-Tetrachloro indane-1,3-dione at 10°C afforded the 2-nitro derivative, m.p. (water, hydrochloric acid) 184°-5°C. (Found; C, 27.89; H, 1.40; N, 3.41; C₉ H Cl₄ NO₄.3H₂ O requires; C, 28.22; H, 1.84; N, 3.66%).

EXAMPLE 11 a. Dimethyl 3,6-dihydro-4,5-dimethyl phthalate

2,3-dimethyl butadiene (30 g; 0.366 mole) and dimethyl acetylene dicarboxylate 47.69 0.366 mole) were heated to 140°C in an autoclave and maintained at the temperature for 4 hrs. After cooling ether was added and the solution filtered. Evaporation of the filtrate afforded the title compound which was recrystallised from methanol; light petroleum (40-60), m.p. 71°-72°C (Found; C, 64.41; H, 7.16; C₁₂ H₁₆ O₄ requires; C, 64.27; H, 7.19%).

b. Dimethyl 4,5-dimethyl phthalate

The above dihydro aromatic compound (50 g.) was added to 10% palladium on charcoal (2.5 g.) and the mixture aerated at 220°-225°C for 3 hrs. After cooling ether was added and the mixture filtered. Evaporation and distillation afforded dimethyl 4,5-dimethyl phthalate, m.p. (methanol, light petroleum (40-60) ) 53°-4°C. (Found: C, 64.87; H, 6.36; C₁₂ H₁₄ O₄ requires: C, 64.85; H, 6.35%).

c. 5,6-Dimethyl indane-1,3-dione

Dimethyl 4,5-dimethyl phthalate (14.6 g; 0.066 mole) in ethyl acetate (20 ml.) was added to a 50% dispersion of sodium hydride in mineral oil (4.63 g; 0.096 mole of NaH) and the mixture refluxed for 4 hrs. on a steam bath. After cooling the yellow solid was filtered and washed with a little cold ethyl acetate. Treatment with a hot (80°C) solution of concentrated hydrochloric acid (20 ml.) in water (200 ml.) for 7 mins. gave the title compound m.p. (benzene) 159°C. (Found: C, 75.77; H, 5.79; C₁₁ H₁₀ O requires: C, 75.84; H, 5.79%).

d. 5,6-Dimethyl-2-nitro-indane-1,3-dione

5,6-dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended in anhydrous ether (5 ml.) was stirred at 10°C during the dropwise addition of fuming nitric acid (1.0 ml.). After the addition was complete the mixture was stirred at ambient temperature for 1 hr. and the precipitated yellow solid filtered. m.p. (water, hydrochloric acid) 111°-113°C. (Found: C, 60.11; H, 4.10; N, 6.14; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N, 6.39%).

EXAMPLE 12 a. 4-Isopropyloxy indane-1,3-dione

Dimethyl 3-isopropyloxy phthalate (41.93 g; 0.166 mole) in ethyl acetate (55 ml) was cautiously added to a 50% dispersion of sodium hydride in mineral oil (11.0 g; 0.228 mole of NaH) and the mixture refluxed for 4 hours on a steam bath. A yellow solid separated which, after cooling, was filtered and washed with a little ethyl acetate. Addition of this solid to 1N hydrochloric acid at 80°C caused immediate dicarboxylation which was complete within 10.15 mins.

After cooling and filtration, recrystallisation (benzene, petroleum (40°-60°) afforded the title product, m.p. 69°-70°C (Found: C, 70.88; H, 5.93; C₁₂ H₁₂ O₂ requires: C, 70.58; H, 5.92%).

b. 4-Isopropyloxy-2-nitro-indane-1,3-dione

4-Isopropyloxy indane-1,3-dione (0.16 g; 0.003 mole) suspended in dry ether (5 ml) was treated dropwise and with stirring with fuming nitric acid (1.0 ml) at 10°C. The resulting dark solution was treated with 5N hydrochloric acid and evaporated to a yellow crystalline product; m.p. (water, hydrochloric acid) 80°-81°C. (Found: C, 57.94; H, 4.43; N, 5.46; C₁₂ H₁₁ NO₅ requires: C, 57.83; H, 4.45; N, 5.62%).

EXAMPLE 13 a. 4,6Dimethyl indane-1,3-dione

Dimethyl 3,5-dimethyl phthalate (15.1 g; 0.068 mole) in ethyl acetate (22 ml.) was treated with a 50% dispersion of sodium hydride in mineral oil (4.80 g; 0.10 mole of NaH) and the mixture refluxed for 4 hrs. at 100°C. After filtration the resulting yellow sodium salt was treated for 7 mins. at 70°-80°C. with hydrochloric acid (11.0 ml.) in water (110 ml.) and the dione product filtered and recrystallised. m.p. (benzene) 137°-138°C. (Found: C, 75.73; H, 5.67; C₁₁ H₁₀ O₂ requires: C, 75.84; H, 5.79%).

b. 4,6-Dimethyl-2-nitro-indane-1,3-dione

4,6-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) suspended in anhydrous ether (5 ml.) was nitrated to the title product as described in Example 12 m.p. (water, hydrochloric acid) 111°-112°C, (Found: C, 60.12, H, 4.16; N, 6.14; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N, 6.39%).

EXAMPLE 14 a. Benz (e) indane-1,3-dione

To a 50% dispersion of sodium hydride in mineral oil (4.55 g) was added to a solution of diethyl naphthalene 1,2-dicarboxylate (18.5 g) in ethyl acetate (22 ml.) and the mixture refluxed for 3.5 hrs. on a steam bath. After cooling the precipitated orange solid was filtered and decarboxylated with hydrochloric acid (35 ml.) in water (350 ml) at 70°C over 7 mins. to yield benze(e) indane-1,3-dione, m.p. (benzene) 178°C (decomp.) (Found: C, 79.21; H, 4.22; C₁₃ H₈ O₂ requires: C, 79.58; H, 4.11%).

b. 2-Nitro benz(e)indane-1,3-dione

Nitration of benz(e) indane-1,3-dione as described in Example 12 afforded the 2-nitro derivative as an orange crystalline solid, m.p. (water, hydrochloric acid) 134.5° - 135.5°C. (Found: C, 64.76; H, 2.91; N, 5.59; C₁₃ H₇ NO₄ requires: C, 64.74; H, 2.93; N, 5.81%).

EXAMPLE 15 a. 3,6-Dimethyl phthalalyl acetic acid

3,6-Dimethyl phthalic anhydride (m.p. 144°-5°C; 15.3 g; 0.087 mole) was treated with freshly fused potassium acetate (13.3 g) and acetic anhydride (27 ml) and heated at 100°C for 1 hr. The mixture was then heated to 150°-155°C at which temperature it was maintained for 4 hours. After cooling, water (80 ml) was added and the brown solid filtered off and washed well with water and cold methanol, After extraction of the residue with 5% sodium bicarbonate followed by acidification of the extract, the title compound was isolated as a yellow solid, m.p. (dioxan) 264°-5°C (Found: C, 66.04; H, 4.69; C₁₂ H₁₀ O₄ requires: C, 66.05; H, 4.62%).

b. 4,7-Dimethyl indane-1,3-dione

Sodium methoxide (from sodium 8.05 g in methanol (80 ml) ) was added with vigorous stirring to a solution of 3,6-dimethyl phthalalyl acetic acid (7.5 g) in methanol (200 ml) and the gel allowed to stand for 2 hrs. The red suspension was then refluxed for 5 hours on a steam bath, cooled and filtered. Addition of the solid to hot (80°C) 5N hydrochloric acid (120 ml) caused immediate decarboxylation and generation of the dione. After cooling the indane dione was filtered, dried, recrystallised, m.p. (benzene) 187°-188°C (Found: C, 75.48; H, 5.88; C₁₁ H₁₀ O₂ requires: C, 75.84; H, 5.79%).

c. 4,7-Dimethyl-2-nitro-indane-1,3-dione

4,7-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was nitrated with fuming nitric acid (1.0 ml) as described in Example 12 to give 4,7-dimethyl-2-nitro-indane-1,3-dione, m.p. (water, hydrochloric acid) 108°-110°C, (Found: C, 60.07; H, 4.20; N, 6.29; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N, 6.39%).

EXAMPLE 16 a. Dimethyl-3-ethyl phthalate

Dimethyl acetylene dicarboxylate (26.0 g; 0.183 mole) was added to a solution of 1,3-hexadine (15.0 g; 0.183 mole) in dry benzene (100 ml) and the mixture stirred in an autoclave at 65°C for 24 hours. Evaporation and distillation then afforded the dihydro aromatic adduct as a colourless oil bp₀.3 mm Hg. 80°-100°C. Aeration of this at 220°-225°C in the presence of 10% palladinised charcoal over 3 hours then afforded, after spinning bend separation, the title compound as a colourless oil bp₁,2 mm Hg. 126°C; (Found: 64.46; H, 6.46; C₁₂ H₁₄ O₄ requires: C, 64.85; H, 6.35%).

b. 4-Ethyl indane-1,3-dione

A solution of dimethyl 3-ethyl phthalate (7.38 g; 0.033 mole) in ethyl acetate (10 ml) was added to a 50% dispersion of sodium hydride in mineral oil (2.32 g) and the mixture reluxed for 4 hours on a steam bath. After cooling the yellow sodium salt was filtered, washed well with dry ether and dried. Treatment with a hot (80°C) solution of hydrochloric acid (10 ml) in water (100 ml) over 10 mins. then gave the requisite dione; m.p. (benzene) 148°C; (Found: C, 76.65; H, 5.45; C₁₁ H₁₀ O₂ requires: C, 75.85; H, 5.80%).

c. 4-Ethyl-2-nitro indane-1,3-dione

A suspension of 4-ethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was treated dropwise at 10°C with fuming nitric acid (1.0 ml) and the precipitated product filtered after 40 mins. at room temperature; m.p. (water, hydrochloric acid) 98°-100°C; (Found; C, 59.98; H, 4.18; N, 6.34; C₁₁ H₉ NO₄ requires: C, 60.28; H, 4.14; N, 6.39%).

EXAMPLE 17 a. 4-Methoxy-6-methyl indane-1,3-dione

Dimethyl 3-methoxy-5-methyl phthalate (14.8 g: 0.062 mole) in ethyl acetate (20 ml) was added to a 50% dispersion of sodium hydride in mineral oil (4.1 g; 0.085 mole) and the mixture refluxed for 4 hours at 100°C. Addition of ether, ethyl acetate to the residual cooled oil afforded a yellow solid which was filtered. Treatment of this solid with 5N hydrochloric acid (30 ml) at 70°C during 7 mins. afforded the title product m.p. (benzene) 172°-3°C (Found: C, 69.45; H, 5.43; C₁₁ H₁₀ O₃ requires; C, 69.46; H, 5.30%).

b. 4-Methoxy-6-methyl-2-nitro indane-1,3-dione

A suspension of 4-methoxy-6-methyl indane-1,3-dione in dry ether was nitrated as in Example 16c to yield the 2-nitro derivative; m.p. (water, hydrochloric acid) 156°-57°C. (Found: C, 56.00; H, 3.86; N, 5.90; C₁₁ H₉ NO₅ requires; C, 56.16; H, 3.86; N, 5.96%).

EXAMPLE 18 a. 6-Ethyl-4-methoxy indane-1,3-dione

Claisen condensation of dimethyl 5-ethyl-3-methoxy phthalate (m.p. 89°C) as given in Example 16b afforded the title product m.p. (benzene, petroleum [40°-60°C ]) 112°-113°C. (Found: C, 70.60; H, 5.97; C₁₂ H₁₂ O₃ requires: C, 70.57; H, 5.92%).

b. 6-Ethyl-4-methoxy-2-nitro indane-1,3-dione

Nitration of a suspension of 6-ethyl-4-methoxy indane-1,3-dione in dry ether as described in Example 16c gave the 2-nitro derivative, m.p. (water, hydrochloric acid) 116°C; (Found: C, 57.85; H, 4.47; N, 5.77; C₁₂ H₁₁ NO₅ requires: C, 57.83; H, 4.45; N, 5.62%).

EXAMPLE 19 a. 5-Phenyl indane-1,3-dione

A solution of dimethyl 4-phenyl phthalate (bp 0.1 170°-80°C) in ethyl acetate was cyclised to the indane dione as described in Example 16b, m.p. (benzene, petroleum [40°-60°]) 116°C. (Found: C, 80.96; H, 4.70; C₁₅ H₁₀ O₂ requires: C, 81.07; H, 4.54%).

b. 2-nitro-5-phenyl indane-1,3-dione

Nitration of 5-phenyl indane-1,3-dione with fuming nitric acid as described in Example 16c gave 2-nitro-5-phenyl indane-1, 3-dione, m.p. (water, hydrochloric acid) 119°C. (Found: C, 65.54; H, 3.39; N, 4.93; C₁₅ H₉ NO₄.1/2 H₂ O requies: C, 65.21; H, 3.65; N, 5.07%).

EXAMPLE 20 a. 4-Isobutyloxy indane-1,3-dione

a solution of dimethyl 3-isobutyloxy phthalate (26.6 g; 0.1 mole; b.p.₀.1 mm Hg 140°-144°C in ethyl acetate (34 ml) was treated with a 50% dispersion of sodium hydride in mineral oil (6.64 g; 0.137 mole) and the brown solution refluxed for 4 hours on a steam bath. The bright yellow solid which separated was filtered aand cleaned by trituration with ethanol: ether (3:1). Decarboxylation with 5N hydrochloric acid (45 ml) at 70°C over 10 min. gave the title dione; m.p. (benzene, petroleum [40°-60°]) 65°C. (Found: C, 71.63; H, 6.52; C₁₃ H₁₄ O₄ requires: C, 71.54; H, 6.47%).

b. 4-Isobutyloxy-2-nitro indane-1,3-dione

4-Isobutyloxy indane-1,3-dione (0.654 g; 0.003 mole) suspended in dry ether (5 ml) was treated dropwise with fuming nitric acid (1.0 ml) at 10°C and the clear dark red solution left to stir at room temperature for 1 hour. Evaporation in the presence of 5N hydrochloric acid gave the 2-nitro derivative as a yellow solid, m.p. (water, hydrochloric acid) 75°-77°C. (Found: C, 58.92; H, 5.00; N, 5.48; C₁₃ H₁₃ NO₅ requires: C, 59.31; H, 4.98; N, 5.32%).

EXAMPLE 21 a. 4-n-Butyloxy indane-1,3-dione

Claisen condensation of dimethyl 3-n-butyloxy phthalate (m.p. 48°C) with ethyl acetate as described in Example 16b afforded the title compound, m.p. (benzene, petroleum [40°-60°]) 66°C. (Found: C, 71.41; H, 6.54; C₁₃ H₁₄ O₄ requires: C, 71.54; H, 6.47%).

b. 4-n-Butyloxy-2-nitro indane-1,3-dione

Nitration of 4-n-butyloxy indane-1,3-dione as described in Example 20b afforded the 2-nitro derivative, m.p. (water, hydrochloric acid) 85°C. (Found: C, 59.07; H, 5.13; N, 5.13; C₁₃ H₁₃ NO₅ requrires: C, 59.31; H, 4.98; N, 5.32%).

EXAMPLE 22 a. 4-n-Propyloxy indane-1,3-dione

Claisen condensation of dimethyl 3-n-propyloxy phthalate with ethyl acetate as described in Example 20a afforded 4-n-propyloxy indane-1,3-dione, m.p. (benzene) 94°-95°C. (Found: C, 70.69; H, 6.05; C₁₂ H₁₂ O₃ requires: C, 70.58; H, 5.92%).

b. 2-Nitro-4-n-Propyloxy indane-1,3-dione

Nitration of 4-n-Propyloxy indane-1,3-dione as described in Example 16c gave the 2-nitro derivative, m.p. (water, hydrochloric acid) 114°-115°C. (Found: C, 57.57; H, 4.43; N, 5.48; C₁₂ H₁₁ NO₅ requires: C, 57.83; H, 4.45; N, 5.62%).

EXAMPLE 23 a. 4-Phenyl indane-1,3-dione

Dimethyl 3-phenyl phthalate (15.0 g; 0.055 mole) in ethyl acetate (20 ml) was added to a 50% dispersion of sodium hydride in mineral oil (3.67 g) and the mixture refluxed for 4 hrs. on a steam bath. Separation of the bright yellow solid followed by decarboxylation with a hot (80°C) solution of hydrochloric acid (25 ml) in water (250 ml) over 7 mins. gave the title product, m.p. (benzene) 125°-128°C (Found: C, 80.94; H, 4.69; C₁₅ H₁₀ O₂ requires C, 81.07; H, 4.54%).

b. 2-Nitro-4-Phenyl indane-1,3-dione

Nitration of 4-phenyl indane-1,3-dione as described in Example 16c afforded the 2-nitro derivative, m.p. (water, hydrochloric acid) 119°C; (Found: C, 67.04; H, 3.37; N, 4.96; C₁₅ H₉ NO₄ requires: C, 67.42; H, 3.39; N, 5.24%).

EXAMPLE 24 Biological Results

All of the 2-nitro indane-1,3-dione prepared in the preceding Examples were submitted for biological testing. The test system was the Rat Passive Cutaneous Anaphylaxis (PCA) test described below in (ii).

i. Serum containing heat labile homocytotropic antibody was raised in rats by a method similar to that used by Mota. (I. Mota Immunology 1964, 7,681).

Male Wistar rats of 250-300 g, were injected intraperitoneally with 0.5 ml of Bordatella pertussis vaccine (containing 4 × 10¹⁰ dead organism per ml) and subcutaneously with 0.5 ml of an emulsion of 100 mg. of ovalbumin in 2 ml of saline and 3 ml of incomplete Freunds' adjuvant. Rats were bled by cardiac puncture on day 18, the blood was pooled and separated and serum stored at -20° and thawed only once before use.

ii. The P.C.A. test was similar to that described by Ovary and Bier (A. Ovary and O. E. Bier, Proc. Soc. Exp.. Biol. Med. 1952, 81, 584) and Goose and Blair (J. Goose and A. M. J. N Blair, Immunolgy 1969, 16, 769).

0.1 ml of each of six twofold serial dilutions of the serum in 0.9% saline were injected intradermally into separate sites on the shaved dorsal surface of 250-350 g. Wistar rats. 72 hours later the animals were challenged by i.v. injection of 0.3 ml of 1% ovalbumin mixed with 0.1 ml of a 5% solution of pontamine sky blue dye both in isotonic saline buffered with pH. 7.2 Sorenson buffer (P.B.S.). The rats were killed after 20 minutes and the diameter of the blue wheals at the antibody injection sites were measured. The starting dilution of the serum was adjusted so that there was no response, after challenge, at the site of injection of the highest dilution and a maximum response at the lowest dilution. Typically, six twofold serial dilutions of the serum from 1/4 to 1/128 were used.

Compounds were tested for their ability to reduce the diameter of the wheels at the injection sites of dilutions of antibody which on all the controls have less than maximum response. Amounts of the compounds were administered to rats each amount to a test group of six animals at a specified time prior to intravenous challenge with ovalbumin. The diameters of the blue wheals which developed on the tests group of animals were compared with those on a control group of six animals treated in the same way as the test group, but which had not received the compound under test.

    % Inhibition of P.C.A. = 100 (1 - a/b)

a = The mean of the sum of the diameters of the wheals produced in the test group of animals at those antibody sites where all the control group of animals gave less than maximum response.

b = The mean of the sum of diameters of the wheals produced in the control group of animals at those antibody sites were all the animals in the group gave less than maximum response.

The preferred method of administration was a solution of the test compound dissolved in pH 7.2 buffer and neutralised with sodium bicarbonate. For those compounds having insoluble sodium salts, the salts were isolated by reaction of the free nitro compound with 2.5N sodium hydroxide and the filtered sodium salt washed free of alkali with water. The dried salts were then administered as a suspension in 1% methyl cellulose.

                                      TABLE I                                      __________________________________________________________________________                             TIME BETWEEN                                                                           INHIBITION                                                             DOSING AND                                                                             OF                                             TEST      FORM IN WHICH                                                                           DOSE CHALLENGE                                                                              PCA RESPONSE                                   COMPOUND  ADMINISTERED                                                                            (mg/kg)                                                                             (MINS)                                                 __________________________________________________________________________     5-bromo-2-                                                                               Solution of Na                                                                          25   0       46                                             nitroindane-1,                                                                           salt     25   60      87                                             3-dione            100  0       30                                                                100  60      64                                             5-methyl-2-                                                                              solution of Na                                                                          25   0       66                                             nitroindane-1,3-                                                                         salt     25   30      44                                             dione              100  0       100                                                               100  30      47                                             4-methyl- Suspension of                                                                           25   0       2                                              2-nitroindane-                                                                           Na salt in 1%                                                                           25   60      33                                             1,3-dione methyl   100  0       6                                                        cellulose                                                                               100  60      57                                             4-methoxy-2-                                                                             Suspension of                                                                           25   0       -2                                             nitroindane-1,                                                                           Na salt in                                                                              25   60      25                                             3-dione   1% methyl                                                                               100  0       18                                                       cellulose                                                                               100  60      36                                             2-nitro-  Suspension of                                                                           25   0       100                                            benz[f] indane-                                                                          Na salt in                                                                              25   60      37                                             1,3-dione 1% methyl                                                                               100  0       100                                                      cellulose                                                                               100  60      72                                             4-bromo-2-                                                                               Suspension of                                                                           25   0       8                                              nitroindane-                                                                             Na salt in 1%                                                                           25   60      24                                             1,3-dione methyl   100  0       -4                                                       cellulose                                                                               100  60      70                                             4,5,6,7-  Solution 25   0       -13                                            tetrachloro-                                                                             of Na    25   60      9                                              2-nitroin-                                                                               salt     100  0       -3                                             dane-1,3-          100  60      7                                              dione                                                                          4-ethoxy-2-                                                                              Solution of                                                                             25   0       13                                             nitroindane-                                                                             Na salt  25   30      68                                             1,3-dione          100  0       76                                                                100  30      55                                             4-fluoro-2-                                                                              Solution of                                                                             25   0       48                                             nitroindane-                                                                             Na salt  25   30      8                                              1,3-dione          100  0       86                                                                100  30      30                                             4-methoxy-7-                                                                             Solution of                                                                             25   0       34                                             methyl-2- Na salt  25   30      62                                             nitroindane-       100  0       36                                             1,3-dione          100  30      44                                             5,6-dimethyl-                                                                            Suspension of                                                                           25   0       92                                             2-nitroindane-                                                                           Na salt in                                                                              25   60      48                                             1,3-dione 1% methyl                                                                               100  0       73                                                       cellulose                                                                               100  60      54                                             4-isopropyloxy-                                                                          Suspension of                                                                           25   0       23                                             2-nitroindane                                                                            Na salt in                                                                              25   30      36                                             1,3-dione 1% methyl                                                                               100  0       49                                                       cellulose                                                                               100  30      51                                             4,6-dimethyl-                                                                            Solution of                                                                             25   0       58                                             2-nitroindane-                                                                           Na salt  25   30      27                                             1,3-dione          100  0       69                                                                100  0       35                                             4,7-dimethyl-                                                                            Suspension of                                                                           25   0       35                                             2-nitroindane-                                                                           Na salt in                                                                              25   60      16                                             1,3-dione 1% methyl                                                                               100  0       46                                                       cellulose                                                                               100  60      8                                              2-nitrobenz(e)                                                                           Suspension of                                                                           25   0       16                                             indane-1,3-                                                                              Na salt in                                                                              25   60      50                                             dione     1% methyl                                                                               100  0       13                                                       cellulose                                                                               100  60      47                                             4-ethyl-2-                                                                               Suspension of                                                                           25   0       - 5                                            nitroindane-1,                                                                           Na salt in                                                                              25   60      23                                             3-dione   1% methyl                                                                               100  0       1                                                        cellulose                                                                               100  60      25                                             4-methoxy-6-                                                                             Solution of                                                                             25   0       34                                             methyl-2- Na salt  25   30      31                                             nitroindane-1,     100  0       80                                             3-dione            100  30      24                                             6-ethyl-4-                                                                               Solution 25   0       66                                             methoxy-2-                                                                               of Na    25   30      37                                             nitroindane-1,                                                                           Salt     100  0       91                                             3-dione            100  30      32                                             2-nitro 5-phenyl                                                                         Suspension                                                                              25   0       58                                             indane-   of Na salt                                                                              25   60      56                                             1,3-dione in 1%    100  0       82                                                       methyl   100  60      36                                                       cellulose                                                            4-isobutyloxy-                                                                           Solution 25   0       61                                             2-nitroindane                                                                            of Na salt                                                                              25   30      28                                             1,3-dione          100  0       78                                                                100  30      41                                             4-n-butyloxy-                                                                            Solution 25   0       29                                             2-nitroindane                                                                            of Na salt                                                                              25   60      43                                             1,3-dione          100  0       63                                                                100  60      50                                             2-nitro-4-                                                                               Solution 25   0       12                                             phenyl indane                                                                            of Na    25   60      22                                             1,3 indione                                                                              Salt     100  0       8                                                                 100  60      24                                             __________________________________________________________________________

EXAMPLE 25 a. 4,5-Cyclohexano indane-1,3-dione.

The Claisen condensation of dimethyl tetralin 5,6-dicarboxylate (11.6 g; 0.0465 mole) with ethyl acetate (15 ml.) as described in example 1b, afforded 4,5-cyclohexano indane-1,3-dione as a yellow crystalline compound, m.p. (benzene) 97°-99°C (Found: C, 77.80; H, 5.74; C₁₃ H₁₂ O₂ requires: C, 77.98; H, 6.04).

b. 4,5-Cyclohexano-2-nitroindane-1,3-dione.

To a stirred suspension of 4,5-cyclohexano indane-1,3-dione (1.0 g; 0.005 mole) in anhydrous ether (8.0 ml.) at -20°C was added fuming nitric acid (1.0 ml.) dropwise. After stirring at 0°-5°C for 1 hr. and then at room temperature for a further 1 hr. water (20 ml.) was added, the ether removed under vacuo and the solution filtered. Addition of concentrated hydrochloric acid to the clear, yellow filtrate afforded the title compound on cooling, m.p. (water, hydrochloric acid) 108°-109°C. (Found: C, 63.67; H, 4.48; N, 5.43; C₁₃ H₁₁ NO₄ requires: C, 63.67; H, 4.72; N, 5.71%).

EXAMPLE 26 a. 4,5-Cyclopentano inane-1,3-dione.

Condensation of dimethyl indane 4,5-dicarboxylate (12.42 g; 0.053 mole) with ethyl acetate as in example 1b gave the dione as a yellow solid, m.p. (benzene, petroleum [40°-60°]) 159°-162°(d). (Found: C, 77.55; H, 5.65; C₁₂ H₁₀ O₂ requires; C, 77.40; H, 5.41%).

b. 4,5-Cyclopentano-2-nitro indane-1,3-dione.

Fuming nitric acid (1.0 ml.) was added dropwise to a stirred suspension of 4,5-cyclopentano indane-1,3-dione (0.95 g; 0.005 mole) in dry ether (8.0 ml.) at 5°-10°C and the mixture stirred at this temperature for 45 mins. Further stirring at room temperature for 1 hr. followed by addition of water (20 ml.), evaporation of ether, and filtration gave a clear, yellow filtrate. Addition of an equal volume of concentrated hydrochloric acid to the latter yielded the 2-nitro derivative as a yellow crystalline solid, m.p. (water, hydrochloric acid) 128°-130°C. (Found: C, 59.96; H, 3.96; N, 5.89: C₁₂ H₉ NO₄.1/2H₂ O requires: C, 60.80; H, 4.20; N, 5.83%).

EXAMPLE 27 a. 5-Methoxy-6-Methyl indane-1,3-dione.

A solution of dimethyl 4-methoxy-5-methyl phthalate (14.21 g; 0.06 mole; m.p. 66°-68°C) in ethyl acetate (20 ml.) was added to a 50% dispersion of sodium hydride in mineral oil (3.95 g; 0.082 mole of NaH) and the mixture refluxed for 4 hrs. The orange-brown sodium salt which separated was broken-up with 1:1 ethanol, ether, filtered and dried in vacuo. Addition of the dried solid to hot (80°C) 5N hydrochloric acid (15 ml.) followed by stirring at 70°C for 7 mins. gave the title dione as a yellow solid, m.p. (benzene) 215°-216°C. (Found: C, 69.11; H, 5.50; C₁₁ H₁₀ O₃ requires: C, 69.46; H, 5.30).

b. 5-Methoxy-6-methyl-2-nitro indane-1,3-dione.

Nitration of 5-methoxy-6-methyl indane-1,3-dione as outlined in examplb 1b gave the 2-nitro derivative as an initially yellow solid which turned orange on dehydration, m.p. 110°C. (Found: C, 56.59; H, 3.83; H, 6.03: C₁₁ H₉ NO₅ requires: C, 56.17; H, 3.86; N, 5.96%).

    Biological Data for Compounds not                                              included in Table I                                                            __________________________________________________________________________                                Time between                                                                          Inhibition                                   Test Compound                                                                            Form in which                                                                             dose  dosing and                                                                            of PCA                                                 administered.                                                                             (mg./kg.)                                                                            challenge                                                                             response                                                                (mins).                                             __________________________________________________________________________     4-n-propyloxy                                                                            Solution of                                                                               25     0     77                                           2-nitroindane-                                                                           sodium salt                                                                               25    30     37                                           1,3-dione.           100    0     30                                                                100   30     37                                           4,5-cyclohexano                                                                          Suspension of                                                                             34     0      7                                           2-nitroindane-                                                                           Na salt in 1%                                                                             34    60     32                                           1,3-dione methyl cellulose                                                     4,5-cyclopentane                                                                         Suspension of Na                                                                          25     0      5                                           2-nitroindane-                                                                           salt in 1% methyl                                                                         25    60     34                                           1,3-dione.                                                                               cellulose  100    0     26                                                                100   60     28                                           __________________________________________________________________________ 

We claim:
 1. A compound of the formula (I) or a pharmaceutically acceptable non-toxic salt thereof: ##SPC9##wherein1or 2 of R₁, R₂, R₃ and R₄ are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy or t-butoxy and the remaining 2 or 3 are each hydrogen or one of R₁, R₂, R₃ and R₄ is fluoro, phenyl or benzyl and the remaining 3 are each hydrogen, or each of R₁, R₂, R₃ and R₄ is chloro, or R₁ and R₂, or R₂ and R₃, or R₃ and R₄ taken together are the residue of a 1,2-phenylene ring or a 1,2-cyclohexylene ring.
 2. 5,6-Dimethyl-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 3. 2-Nitrobenz indane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 4. 4-Methoxy-6-ethyl-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 5. 4-n-Butoxy-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 6. 4,6-Dimethyl-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 7. 5-Methyl-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 8. 4-fluoro-2-nitroindane-1,3-dione or a pharmaceutically acceptable non-toxic salt thereof.
 9. The compound according to claim 1 which is 4-methoxy-2-nitroindane-1,3-dione.
 10. The compound according to claim 1 which is 4-ethoxy-2-nitroindane-1,3-dione.
 11. The compound according to claim 1 which is 4-methoxy-7-methyl-2-nitroindane-1,3-dione.
 12. The compound according to claim 1 which is 2-nitro-4,5,6,7-tetrachloroindane-1,3-dione.
 13. The compound according to claim 1 which is 4-isopropyloxy-2-nitroindane-1,3-dione.
 14. The compound according to claim 1 which is 2-nitro-benz(e) indane-1,3-dione.
 15. The compound according to claim 1 which is 4,7-dimethyl-2-nitroindane-1,3-dione.
 16. The compound according to claim 1 which is 4-ethyl-2-nitroindane-1,3-dione.
 17. The compound according to claim 1 which is 4-methoxy-6-methyl-2-nitroindane-1,3-dione.
 18. The compound according to claim 1 which is 2-nitro-5-phenylindane-1,3-dione.
 19. The compound according to claim 1 which is 4-isobutyloxy-2-nitroindane-1,3-dione.
 20. The compound according to claim 1 which is 2-nitro-4-n-propyloxyindane-1,3-dione.
 21. The compound according to claim 1 which is 2-nitro-4-phenylindane-1,3-dione. 